Gaucher's disease
Gaucher's disease is a rare inherited disorder caused by a genetic defect leading to a deficiency of the enzyme glucocerebrosidase, which is crucial for breaking down specific lipids in the body. This deficiency results in the accumulation of glucosyl ceramide sphingolipids, primarily affecting the liver, spleen, and bone marrow, classified as a lysosomal storage disease. Symptoms vary depending on the type of Gaucher's disease, with Type I being the most common form characterized by liver and spleen enlargement, bone marrow abnormalities, severe anemia, and bleeding issues, without neurological symptoms. In contrast, Type II is a severe infantile form that typically leads to significant neurological damage and early mortality, while Type III presents a less severe outcome with neurological involvement.
Treatment options have evolved significantly, with enzyme replacement therapy being developed in the 1990s to address the enzyme deficiency by administering glucocerebrosidase. This therapy has been effective for many patients with Type I disease but less so for others. Newer oral medications have also been introduced, enhancing treatment efficacy, particularly for Type I and Type III forms. Despite advancements, no effective treatment exists for Type II, which underscores the complexity of the disease and the need for ongoing research. Genetic testing and prenatal screening are available to assess risks in affected populations, notably among Ashkenazi Jews, where the incidence is notably higher.
Gaucher's disease
ANATOMY OR SYSTEM AFFECTED: Abdomen, bones, cells, liver, lymphatic system, spleen
DEFINITION: A congenital disorder caused by a defect in lipid metabolism and characterized by cell hyperplasia in the liver, spleen, and bone marrow.
CAUSES: Genetic enzyme deficiency
SYMPTOMS: Varies with type; may include liver and spleen enlargement, bone marrow abnormalities, severe anemia, severe bleeding, central nervous system damage
DURATION: Chronic
TREATMENTS: Enzyme replacement therapy, genetically engineered drugs
Causes and Symptoms
Gaucher’s disease (also referred to as Gaucher disease) is an inherited disorder resulting from a in the gene that encodes the enzyme glucocerebrosidase, one of a class of enzymes that functions in the breakdown (hydrolysis) of glucosyl ceramide lipids. The result is an accumulation of a class of known as glucosyl ceramide sphingolipids, primarily in cells of the liver, spleen, or bone marrow. Normally, these lipids are hydrolyzed within digestive called lysosomes, found within these cells. The buildup of lipids within these structures classifies Gaucher’s disease as a form of lysosomal storage disease; cells in which these pathologies are presented are known as Gaucher cells.
Gaucher’s disease is not common in the general population and affects approximately 1 in 60,000 persons, although three to four times that number probably carry one copy of the defective gene. However, in the ethnic population of Ashkenazi (Eastern European) Jews, approximately 1 in 450 persons is afflicted with the disease, making it among the most common genetic disorders in this group. In 2024, the National Gaucher Foundation, an organization that monitors the disorder, estimated that approximately 2,500 Americans had the disease.
Three different types of Gaucher’s disease have been described, differing in their severity, in the presence or absence of neurological defects, and in the general demographics of the disorder. The most common form is Type I, characterized by of the liver and and accompanied by abnormalities; neurological problems are not observed in this form. Its symptoms include severe anemia, attributable to pathological events among the bone marrow precursors; low numbers of platelets, resulting in severe bleeding; and significant hyperplasia in the spleen and liver. The disease, when observed, is generally found in the adult population, though not all persons with this genetic mutation actually experience all, or even any, of the symptoms. Type II (infantile) disorder, a neuropathic or malignant presentation, is a significantly more severe form that affects children under the age of six months; rarely do these children survive beyond two years as a result of significant damage, especially among the cranial nerves. The third form, Type III (juvenile), is less severe than Type II and significantly more in its prognosis; children can usually grow into their adult years.
Treatment and Therapy
Until the 1990s, control of Gaucher’s disease involved a combination of and repeated blood transfusions. The development of enzyme replacement therapy in 1991 provided a means of controlling the disease through the direct presentation of the missing enzyme glucocerebrosidase to the patient’s system. The enzyme was obtained and purified from human placentas collected following hospital births. The initial studies using the natural form of glucocerebrosidase were disappointing, but a chemically modified product proved more successful. The modified form of the enzyme was presented intravenously to persons on an outpatient basis approximately twice each month. Though costly, the process proved effective in controlling most forms of Type I disease, the most common, but less effective for other forms of the disease. In those patients for whom therapy had proven effective, other aspects of the disorder such as cell hyperplasia were often reversed.
Treatments developed in the late 1990s included genetically engineered forms of drugs that could be taken orally. This form of treatment has proven highly effective with those expressing the Type I form and to a lesser extent the Type III form. In addition to replacement of the defective enzyme, a new class of drugs was also developed that inhibited the actual synthesis of the potentially toxic lipids by blocking the action of the enzyme glucosylceramide synthase.
No effective treatment exists for the Type II form of Gaucher’s disease, and central damage is not reversible, even if the disease does respond to therapy.
Perspective and Prospects
Since the chromosomal site of Gaucher’s disease is known—chromosome 1q21, or the long arm of chromosome number 1—prenatal testing is possible to determine whether the developing carries the defective gene. The course, or any decision with regard to treatment, is difficult because of the variable nature of many forms of the disease. Carriers can be observed through the use of molecular techniques, such as restriction fragment length polymorphisms (RFLPs), which detect the presence of abnormal forms of the affected gene. However, even within the population affected, such as Ashkenazi Jews, multiple forms of mutations can be found. The significance of different mutations within the same gene remains confusing, in that different persons with even similar defects may manifest the disease in a variety of forms. Clearly, the role of other factors in the expression of Gaucher’s disease remains to be clarified.
The disease is not manifested in every individual carrying the mutation; genetic testing of parents in at-risk groups, or the testing of normal parents who have a child with the disorder, may also provide a means of during for the possibility of illness in the developing child. Given the variable nature of the disease, the issue of screening remains controversial.
Ideally, gene replacement remains the only method, which, in theory, could cure the disease. The aspect of the disorder, however, means that even if possible, replacement would have to be carried out in utero. For the near future, treatment and control rest upon an increasingly effective use of oral drugs to compensate for the absent enzyme.
Bibliography
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